US3997539A - 3-(4-Acylaminopiperazin-1-yl alkyl)indoles, precursors and processes for the preparation thereof - Google Patents

3-(4-Acylaminopiperazin-1-yl alkyl)indoles, precursors and processes for the preparation thereof Download PDF

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Publication number
US3997539A
US3997539A US05/475,315 US47531574A US3997539A US 3997539 A US3997539 A US 3997539A US 47531574 A US47531574 A US 47531574A US 3997539 A US3997539 A US 3997539A
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ethyl
indole
compound
carbon atoms
group
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US05/475,315
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English (en)
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Edward J. Glamkowski
Philip A. Reitano
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CNA Holdings LLC
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American Hoechst Corp
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Priority to US05/475,315 priority Critical patent/US3997539A/en
Priority to DE19752522143 priority patent/DE2522143A1/de
Priority to NL7506167A priority patent/NL7506167A/xx
Priority to FR7516760A priority patent/FR2272673A1/fr
Priority to LU72609A priority patent/LU72609A1/xx
Priority to DK244275A priority patent/DK244275A/da
Priority to JP50064422A priority patent/JPS511485A/ja
Priority to AT414375A priority patent/ATA414375A/de
Priority to GB23646/75A priority patent/GB1513883A/en
Priority to BE156956A priority patent/BE829786A/xx
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Publication of US3997539A publication Critical patent/US3997539A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to 3-(4-acylaminopiperazin-1-ylalkyl)indoles and immediate precursors, and their physiologically acceptable salts; these indoles, whether final products or precursors, possess antihypertensive and tranquilizing activity.
  • a method for their preparation is within the scope of this invention. It is believed that the compounds of this invention have not heretofore been described.
  • 3-Indolylalkyl-amines are known and have been shown to possess important biological activity.
  • Benzamidopiperidylethylindoles are reported to be potent antihypertensive agents [Archibald et al., J. Med. Chem., 14, 1054 (1971)]
  • 1-[(3-indole)alkyl]-4-arylpiperazines are reported to be active as central nervous system depressants [Wylie et al., J. Med. Phar. Chem., 5, 932 (1962)].
  • the compounds of the invention are represented by the formula: ##STR3## and the formula ##STR4## wherein X represents hydrogen or hydroxy, n can vary from 0-1, R 1 and R 2 each represents hydrogen or alkoxy of 1-2 carbon atoms, R 3 represents hydrogen or alkyl of 1-3 carbon atoms; and R 4 represents alkyl of 1-4 carbon atoms, benzhydryl, cycloalkyl of 6-10 carbon atoms, bridged cycloalkyl of 6-10 carbon atoms with the bridging member having from 1-3 carbon atoms, phenyl, mono, di or tri substituted phenyl and heterocyclic moieties such as pyridyl, furyl, pyrroloyl, thienyl, pyrazinyl, preferably furyl or substituted furyl; and physiologically tolerable addition salts, i.e., acceptable addition salts of the above compounds are also within the scope of the invention.
  • R 4 represents a substituted phenyl
  • the substituents can be on any of the five available positions of the benzene ring and the substituents can be a halogen, straight or branched chain alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, trifluoromethyl, nitro, phenyl, sulfamyl, or hydroxy
  • R 4 represents substituted furyl
  • the substituents may be on the three available positions and may be halo, preferably bromo, or lower alkyl, preferably methyl; of the above indole compounds those where n is 1 and X is hydrogen including where R 1 and R 2 each is hydrogen and R 3 is hydrogen and methyl are preferred; of this group, the substituents where R 4 is substituted or unsubstituted furyl and phenyl are the most preferred compounds.
  • the indole compounds where n is 0 and X is hydrogen is a desirable group, the other substituents in this
  • the compounds of the present invention are prepared by one of three multi-step sequence of reactions as described below and illustrated in the attached drawings, with the exceptions noted in the drawings, in which X, n, R 1 , R 2 , and R 3 , and R 4 are as defined above.
  • 3-[2-(4-acylaminopiperazin-1-yl)ethyl]indoles of the formula: ##STR5## wherein n is 1, are prepared by the following sequence designated as Method A and shown in FIG. 1. Starting with the substituted indoles known in the literature, the 3-(indolyl)glyoxalyl halides of formula I(a) are prepared by the method of Speeter et al., J. Am. Chem. Soc., 76, 6209 (1954).
  • the intermediates so prepared are reacted with N-nitrosopiperazine at a temperature between -10° to 100° C. to give the 3-1-(indol-3-ylglyoxyloyl)-4-nitrosopiperazines of formula II(a).
  • This reaction may or may not be carried out in a solvent or mixture of solvents.
  • An added inorganic base such as potassium carbonate, or an organic base such as triethylamine, may be used to bind the hydrogen halide liberated during the course of the reaction; and added base is optional because N-nitrosopiperazine itself can serve as the hydrogen ion acceptor.
  • the reaction is carried out by adding the 3-(indolyl)glyoxalyl halide to a chloroform and water mixture containing the N-nitrosopiperazine and potassium carbonate while maintaining the temperature at 20°-25° C. over a span of from 1 minute to 60 minutes.
  • certain acid sensitive indoles such as when R 1 and R 2 represent methoxy and R 3 represents methyl, it may be advantageous to combine the first two steps of this method in one reaction vessel without isolating their sensitive intermediate of formula I(a).
  • lithium aluminum hydride is used as the reducing agent and 1,2-dimethoxyethane is the solvent, and the mixture is refluxed to produce a nearly quantitative yield of a compound designated as III(a), i.e., one of the novel compounds herein.
  • a 3-dimethylaminomethylindole is allowed to react with N-nitrosopiperazine in an inert solvent for 1-48 hours to produce the 3-(4-nitrosopiperazin-1-yl) methylindoles in high yields.
  • a preferred embodiment utilizes toluene as the inert solvent at refluxing conditions for 1-2 days.
  • Reduction with an alkali metal hydride in an appropriate inert solvent produces the 3-(4-aminopiperazin-1-yl) methylindoles, compounds of this invention of the formula III(c) illustrated in FIG. 3.
  • this reduction is effected with lithium aluminum hydride in 1,2-dimethoxyethane by refluxing for from 0.5 hour-6 hours.
  • the pharmaceutically acceptable, i.e., tolerable, acid addition salts of the 3-(4-amino and the 3-(4-acylaminopiperazin-1-yl) alkylindoles which are prepared according to well known procedures.
  • Representative of such salts are those formed with mineral acids, such as the hydrochloride, hydrobromide, sulfate, phosphate and the like, and the organic acid salts, such as the maleate, oxalate, succinate, pamoate, p-toluenesulfonate, and the like.
  • the compounds of this invention are useful as antihypertensive agents due to their ability to depress blood pressure in mammals.
  • Antihypertensive activity was measured in the spontaneous hypertensive rat by the indirect tail cuff method described in A. Schwartz, Ed., Methods in Pharmacology, Vol. I, page 135, Appleton-Century Crofts, New York, New York, 1971.
  • systolic blood pressure readings were made at 0 time (control) on days 1 and 3. Dosing was orally at 100 mg/kg at 0 hour on days 1, 2 and 3 on groups of 6 animals per test. Activity was determined by comparison of the treated host's blood pressure values with the 0 time (control) blood pressure readings. A value of -15 mm Hg or more is considered significant.
  • Compounds of the invention are also useful as tranquilizing agents because of their depressant effects on the central nervous system. These tranquilizing effects were measured according to the mouse observation procedure of S. Irwin, Psychopharmacologia, 9, 259 (1966). In this test, male mice (type COBS) were dosed orally with the drug and its effects on behavior and reflex depression, together with muscle relaxation, were determined by the degree of deviation from control scores. The overall result for 3 animals in each category for some compounds of this invention is expressed in terms of the minimum effective dose (MED) and is illustrated in Table II.
  • MED minimum effective dose
  • Effective quantities in the range from 0.1-100 mg/kg body weight of any of the pharmacologically active 3-(4-acylaminopiperazin-1-ylalkyl)indoles may be administered to a patient by any one of various methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intraveneously in the form of sterile solutions.
  • the free base final products while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility and the like.
  • the active compounds of the present invention may be orally administered, for example, with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules, or they may be compressed into tablets.
  • the active compounds of the invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like. These preparations should contain at least 0.5% of active compound, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained.
  • Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 0.1-100 milligrams of active compound.
  • the tablets, pills, capsules, troaches, and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like; a lubricant such as magnesium stearate or Sterotex; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like
  • a lubricant such as magnesium stearate or Sterotex
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent
  • dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
  • tablets or pills may be coated with sugar, Shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent, and certain preservatives, dyes and colorings, and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • the carrier or excipient may be a sterile, parenterally acceptable liquid; e.g., water or a parenterally acceptable oil, e.g., arachis oil contained in ampules.
  • p-isopropylbenzaldehyde is oxidized to the corresponding benzoic acid by using potassium permanganate in sulfuric acid as the oxidizing agent at low temperature.
  • the acid is converted to the acid chloride using thionyl chloride with a trace of dimethylformamide as a catalyst to give p-isopropylbenzoyl chloride.
  • the partially reduced product is separated from the totally reduced material by crystallization from ethanol to give pure crystals of 3-[1-hydroxy-2-(4-aminopiperazin-1-yl) ethyl]indole, m.p. 174°-177° C. Analysis: Calculated for C 14 H 20 N 4 O: 64.59% C 7.74% H; 21.52% N Found: 64.54% C; 7.84% H; 21.80% N.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Furan Compounds (AREA)
US05/475,315 1974-05-31 1974-05-31 3-(4-Acylaminopiperazin-1-yl alkyl)indoles, precursors and processes for the preparation thereof Expired - Lifetime US3997539A (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
US05/475,315 US3997539A (en) 1974-05-31 1974-05-31 3-(4-Acylaminopiperazin-1-yl alkyl)indoles, precursors and processes for the preparation thereof
DE19752522143 DE2522143A1 (de) 1974-05-31 1975-05-17 3-(4-acylaminopiperazin-1-yl-alkyl)- indole und verfahren zu ihrer herstellung
NL7506167A NL7506167A (nl) 1974-05-31 1975-05-26 Werkwijze voor het bereiden van 3-(4-acyl- aminopiperazine-1-ylalkyl)-indolen en voor- lopers daarvan.
LU72609A LU72609A1 (enrdf_load_stackoverflow) 1974-05-31 1975-05-29
FR7516760A FR2272673A1 (enrdf_load_stackoverflow) 1974-05-31 1975-05-29
DK244275A DK244275A (da) 1974-05-31 1975-05-30 3-(4-aminopiperazin-1-yl-alkyl)-indol-forbindelser samt fremgangsmade til deres fremstilling og anvendelse
JP50064422A JPS511485A (enrdf_load_stackoverflow) 1974-05-31 1975-05-30
AT414375A ATA414375A (de) 1974-05-31 1975-05-30 Verfahren zur herstellung von neuen 3-(4-acylaminopiperazin-1-yl-alkyl)-indolen sowie deren saeureadditionssalzen
GB23646/75A GB1513883A (en) 1974-05-31 1975-05-30 3-(4-amino-and 4-acylamino-piperazin-1-ylalkyl)indoles
BE156956A BE829786A (fr) 1974-05-31 1975-06-02 3-(4-acylaminopiperazin-1-ylalcoyl) indoles, leurs precurseurs, leurs preparation et leurs applications

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US05/475,315 US3997539A (en) 1974-05-31 1974-05-31 3-(4-Acylaminopiperazin-1-yl alkyl)indoles, precursors and processes for the preparation thereof

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US (1) US3997539A (enrdf_load_stackoverflow)
JP (1) JPS511485A (enrdf_load_stackoverflow)
AT (1) ATA414375A (enrdf_load_stackoverflow)
BE (1) BE829786A (enrdf_load_stackoverflow)
DE (1) DE2522143A1 (enrdf_load_stackoverflow)
DK (1) DK244275A (enrdf_load_stackoverflow)
FR (1) FR2272673A1 (enrdf_load_stackoverflow)
GB (1) GB1513883A (enrdf_load_stackoverflow)
LU (1) LU72609A1 (enrdf_load_stackoverflow)
NL (1) NL7506167A (enrdf_load_stackoverflow)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA795239B (en) * 1978-10-12 1980-11-26 Glaxo Group Ltd Heterocyclic compounds
GB8917687D0 (en) * 1989-08-02 1989-09-20 Fujisawa Pharmaceutical Co Aminopiperazine derivatives,processes for preparation thereof and pharmaceutical composition comprising the same
US6011035A (en) * 1998-06-30 2000-01-04 Neuromed Technologies Inc. Calcium channel blockers
US6310059B1 (en) 1998-06-30 2001-10-30 Neuromed Technologies, Inc. Fused ring calcium channel blockers
US6951862B2 (en) 1998-06-30 2005-10-04 Neuromed Technologies, Inc. Calcium channel blockers comprising two benzhydril moieties
US6943168B2 (en) 1998-06-30 2005-09-13 Neuromed Technologies Inc. Calcium channel inhibitors comprising benzhydril spaced from piperazine
US6387897B1 (en) 1998-06-30 2002-05-14 Neuromed Technologies, Inc. Preferentially substituted calcium channel blockers
US7186726B2 (en) 1998-06-30 2007-03-06 Neuromed Pharmaceuticals Ltd. Preferentially substituted calcium channel blockers
US6492375B2 (en) 1998-06-30 2002-12-10 Neuromed Technologies, Inc. Partially saturated calcium channel blockers

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2663706A (en) * 1951-06-22 1953-12-22 American Cyanamid Co 1-substituted-4-aminopiperazines and method of preparing the same
US2663707A (en) * 1951-06-22 1953-12-22 American Cyanamid Co Amino piperazines and methods of preparing the same
US3188313A (en) * 1959-09-25 1965-06-08 Sterling Drug Inc 1-[(1-, 2- and 3-indolyl)-lower]piperazine derivatives and intermediates and processes for the preparation thereof
US3297689A (en) * 1965-01-05 1967-01-10 Searle & Co 1-arylidenemaino-4-(4-benzhydryl-1-piperazinylcarbonyl) piperazines and intermediate herefor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2663706A (en) * 1951-06-22 1953-12-22 American Cyanamid Co 1-substituted-4-aminopiperazines and method of preparing the same
US2663707A (en) * 1951-06-22 1953-12-22 American Cyanamid Co Amino piperazines and methods of preparing the same
US3188313A (en) * 1959-09-25 1965-06-08 Sterling Drug Inc 1-[(1-, 2- and 3-indolyl)-lower]piperazine derivatives and intermediates and processes for the preparation thereof
US3297689A (en) * 1965-01-05 1967-01-10 Searle & Co 1-arylidenemaino-4-(4-benzhydryl-1-piperazinylcarbonyl) piperazines and intermediate herefor

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Publication number Publication date
BE829786A (fr) 1975-12-02
FR2272673A1 (enrdf_load_stackoverflow) 1975-12-26
JPS511485A (enrdf_load_stackoverflow) 1976-01-08
DK244275A (da) 1975-12-01
GB1513883A (en) 1978-06-14
ATA414375A (de) 1978-05-15
DE2522143A1 (de) 1975-12-18
NL7506167A (nl) 1975-12-02
LU72609A1 (enrdf_load_stackoverflow) 1977-02-11

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